| 3,4-disubstituted coumarin and quinolone compounds -> Monitor Keywords |
|
|
 
3,4-disubstituted coumarin and quinolone compoundsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Nitrogen Containing Hetero Ring, Polycylo Ring System Having A Ring Nitrogen In The System3,4-disubstituted coumarin and quinolone compounds description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060223783, 3,4-disubstituted coumarin and quinolone compounds. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to 3,4-disubstituted coumarin and quinolone derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 3,4-disubstituted coumarin or quinolone derivative. The invention provides a synthetic process for the preparation of 3,4-disubstituted coumarin and quinolone derivatives using mild reaction conditions, which provides a high substituent tolerance and is appropriate for use in solid phase syntheses for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening. BACKGROUND OF THE INVENTION [0002] Strategies in new drug discovery often look to natural products for leads in finding new chemical compounds with therapeutic properties. One of the recurring problems in drug discovery is the availability of organic compounds derived from natural sources. Techniques employing combinatorial chemistry attempt to overcome this problem by allowing the high throughput synthesis and testing of hundreds or thousands of related synthetic compounds, called a chemical library. In designing the synthesis of a prospective therapeutic compound or a chemical library, one often looks to natural chemical motifs which are known to have broad biological activity. Coumarin and Quinolone derivatives are of particular interest due to their frequent occurrence in nature and range of biological activities. [0003] Coumarins are widely distributed in the plant kingdom. Approximately 50 naturally occurring coumarin derivatives have been identified. Derivatives of both coumarin and quinolone posses a range of biological activities. To avoid confusion, the coumarin and quinolone derivatives described herein are numbered according to the following convention: [0004] Infection with the Hepatitis C virus (HCV) represents a serious world-wide health crisis. In more than 70% of infected individuals, the virus evades clearance by the immune system leading to a persistent HCV infection. The long term effects of persistent HCV infection range from an apparently healthy carrier state to chronic hepatitis, liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma. HCV is a leading cause of chronic liver disease. The best therapy currently available for treatment of HCV infection uses a combination of pegylated .alpha.-interferon and ribavirin. However, many of the patients treated with this therapy fail to show a sufficient antiviral response. Additionally, interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Thus, it is vital that more effective treatments be identified. SUMMARY OF THE INVENTION [0005] The present invention provides 3,4-disubstituted coumarin and quinolone derivatives having the formula I wherein: [0006] each R.sup.1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, --O--R.sup.11, --N(R.sup.12)(R.sup.13), --N(R.sup.11)C(O)R.sup.11, --N(R.sup.11)SO.sub.2R.sup.11, --SR.sup.11, --C(O)R.sup.11, --C(O)OR.sup.11, --C(O)N(R.sup.12)(R.sup.13), --OC(O)R.sup.11, --OC(O)N(R.sup.12)(R.sup.13), CN, CF.sub.3, NO.sub.2, SO.sub.2, --SOR.sup.11, --SO.sub.3R.sup.11, --SO.sub.2N(R.sup.12)(R.sup.13), -alkyl-O--R.sup.11, cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and heteroaryl; [0007] additionally or alternatively two R.sup.1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R.sup.1; [0008] each R.sup.11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; [0009] each R.sup.12 and R.sup.13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R.sup.12 and R.sup.13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom, [0010] n is 0 to 4; [0011] R.sup.2 is selected from the group consisting of aralkyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl; [0012] R.sup.3 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, --(CH.sub.2).sub.aC(O)R.sup.31, --(CH.sub.2).sub.aC(O)N(R.sup.32)(R.sup.33), (CH.sub.2).sub.aC(O)OR.sup.31, --(CH.sub.2).sub.aC(O)N(R.sup.32)(R.sup.33), --(CH.sub.2).sub.aN(R.sup.32)(R.sup.33), --CH.dbd.N--R.sup.34, [0013] R.sup.31 selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; [0014] R.sup.32 and R.sup.33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; [0015] or R.sup.32 and R.sup.33 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; [0016] R.sup.34 is selected from alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl [0017] a is 0 to 6; [0018] X is selected from O and N--R.sup.4; [0019] R.sup.4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, --(CH.sub.2).sub.bC(O)R.sup.41, --(CH.sub.2).sub.bC(O)N(R.sup.42)(R.sup.43), --(CH.sub.2).sub.bC(O)OR.sup.41, and --(CH.sub.2).sub.bC(O)N(R.sup.42)(R.sup.43), [0020] each R.sup.41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; [0021] R.sup.42 and R.sup.43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; [0022] or R.sup.42 and R.sup.43 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; [0023] b is 0 to 6; [0024] Y is selected from O and N--R.sup.5; [0025] R.sup.5 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, --(CH.sub.2).sub.bC(O)R.sup.51, --(CH.sub.2).sub.bC(O)N(R.sup.52)(R.sup.53), and --(CH.sub.2).sub.bC(O)OR.sup.51; [0026] each R.sup.51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; [0027] R.sup.52 and R.sup.53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; [0028] or R.sup.52 and R.sup.53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and [0029] b is 0 to 6; [0030] or a pharmaceutically acceptable salt or hydrate thereof. [0031] The invention also provides a synthetic process for the preparation of compounds of the formula I. The process uses mild reaction conditions, which provides a high substituent tolerance. Thus, the process is applicable to the preparation of a wide variety of 3,4-disubstituted coumarin and quinolone derivatives with diverse substitution patterns. Additionally, the process is appropriate for use with combinatorial synthesis techniques. Thus, the process provides a method for producing a library of 3,4-disubstituted coumarin and quinolone derivatives for biological screening. [0032] The invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention in a therapeutically effective amount. DETAILED DESCRIPTION OF THE INVENTION [0033] The term "halo" or "halogen" as used herein includes fluorine, chlorine, bromine and iodine. [0034] The term "alkyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms. The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. The alkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0035] The term "alkenyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals containing from two to 8 carbon atoms. The alkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0036] The term "alkynyl" as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to 8 carbon atoms and having at least one carbon-carbon triple bond. The term alkynyl includes, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-1-butynyl, and the like. The alkynyl group may be optionally substituted with one or more substituents selected from halo, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0037] The term "cycloalkyl" as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing form 3 to 7 carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl. [0038] The term "cycloalkenyl" as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing form 5 to 7 carbon atoms in which has a double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl, and the like. The cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl. [0039] The term "aralkyl" as used herein contemplates a lower alkyl group which has as a substituent an aromatic group, which aromatic group may be substituted or unsubstituted. The aralkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0040] The terms phosphate and phosphonate as used herein refer to the moieties having the following structures, respectively: [0041] The term "heterocyclic group" or "heterocyclic ring" as used herein contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing 5 or 6 ring atoms which includes at least one hetero atom, and includes cyclic amines such as morpholino, piperidino, pyrrolidino, and the like, and cyclic ethers, such as tetrahydrofuran, tetrahydropyran, and the like. Aromatic heterocyclic groups, also termed "heteroaryl" groups contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. The term heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like. The heterocyclic group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0042] The terms "aryl", "aromatic group", or "aromatic ring" as used herein contemplates substituted or unsubstituted single-ring aromatic groups (for example, phenyl, pyridyl, pyrazole, etc.) and polycyclic ring systems (naphthyl, quinoline, etc.). The polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. The aryl group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R')(R''), --N(R)C(O)R, --N(R)SO.sub.2R, --SR, --C(O)N(R')(R''), --OC(O)R, --OC(O)N(R')(R''), SO.sub.2, --SOR, --SO.sub.3R, --SO.sub.2N(R')(R''), phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0043] Each R is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl. Each R' and R'' are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R' and R'' may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom. [0044] The term "heteroatom", particularly as a ring heteroatom, refers to N, O, and S. [0045] All value ranges, for example those given for n and m, are inclusive over the entire range. Thus, a range of 0 to 4 would include the values 0, 1, 2, 3 and 4. Continue reading about 3,4-disubstituted coumarin and quinolone compounds... Full patent description for 3,4-disubstituted coumarin and quinolone compounds Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this 3,4-disubstituted coumarin and quinolone compounds patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like 3,4-disubstituted coumarin and quinolone compounds or other areas of interest. ### Previous Patent Application: 2-methylene-19-nor-(23s)-25-dehydro-1alpha-hydroxyvitamin d3-26,23-lactone and 2-methylene-19-nor-(23r)-25-dehydro-1alpha-hydroxyvitamin d3-26,23-lactone Next Patent Application: Method and compositions for temporarily incapacitating subjects Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the 3,4-disubstituted coumarin and quinolone compounds patent info. IP-related news and info Results in 0.13351 seconds Other interesting Feshpatents.com categories: Novartis , Pfizer , Philips , Polaroid , Procter & Gamble , 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
